A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation
- Gerasimos Langousis
- Pablo Gainza
- Moritz Hunkeler
- Despoina Kapsitidou
- Etienne J. Donckele
- Stefano Annunziato
- Lars Wiedmer
- Katherine F. M. Jones
- Bradley DeMarco
- Chao Quan
- Richard D. Bunker
- Kevin J. Lumb
- Bernhard Fasching
- John C. Castle
- Sharon A. Townson
- Debora Bonenfant
2025-11-19
Cereblon (CRBN) is an E3 ubiquitin ligase widely harnessed for targeted protein degradation (TPD). We report the discovery of a molecular glue degrader (MGD), MRT-31619, that drives homo-dimerization of CRBN and promotes its fast, potent, and selective degradation by the ubiquitin proteasome system. Interestingly, the cryo-electron microscopy (cryo-EM) structure of the CRBN homodimer reveals a unique mechanism whereby two molecular glues assemble into a helix-like structure and drive ternary complex formation by mimicking a neosubstrate G-loop degron. This CRBN chemical knockout offers a valuable tool to elucidate the molecular mechanism of MGDs, to investigate its endogenous substrates and understand their physiological roles.